Following the birth of an infant, 10-15% of women experience postpartum depression (PPD) (Halbreich &Karkum, 2006). Understanding the basic functional neuroendocrinology of the postpartum period, including hormonally mediated patterns of neural activation in response to negatively arousing stimuli, is imperative for appropriate treatment. Studies of depression in women outside of the postpartum period have shown that depressed women exhibit altered prefrontal-limbic system neural activation patterns and increased reactivity to negative stimuli (Liberzon &Martis, 2006;Siegle et al., 2007). Whether the same is true of women suffering from PPD is not known. Importantly, the prefrontal-limbic system may mediate maternal behavior (Lorberbaum et al., 1999, Ranote et al., 2004;Seifritz et al., 2003;Swain et al., 2007). A working hypothesis is that the prefrontal-limbic system is altered by motherhood, becoming more sensitive to infant stimuli and less responsive to negatively arousing stimuli in the environment. The neuropeptide oxytocin is known to decrease neural activation in the limbic system (Kirsch et al., 2005) and is elevated in new mothers, suggesting that it may be important to the change in functional reactivity in postpartum women. If altered responsiveness of the prefrontal-limbic system to negative stimuli is critical for optimal maternal behavior, then the disruption of this circuitry previously demonstrated in depressed women (Herwig et al., 2007;Siegle et al., 2007) may have important implications for the mental health of postpartum women and their infants. The current study proposes to investigate whether there is an oxytocin-mediated inhibition of the neural response to negatively arousing stimuli in nondepressed postpartum breast-feeding women, and whether this inhibition is disrupted in women with PPD. Using functional magnetic resonance imaging (fMRI), we will first characterize neural activation of nondepressed postpartum women in response to negatively arousing stimuli and compare their activation to the neural activity in postpartum women with PPD. Endogenous levels of oxytocin will be correlated with brain activation to look for an association between the two. To investigate potential causation of oxytocin action in the brain on women's responses to negatively arousing stimuli, we will also measure the neural activation of women given exogenous nasal oxytocin spray. Specifically, the brain activity of 36 nulliparous women, 36 nondepressed postpartum women, and 36 depressed postpartum women will be compared in their response to negatively arousing pictures. Within each of the three groups, 12 women will be tested without intervention, 12 will receive placebo nasal spray, and 12 will receive nasal oxytocin spray prior to fMRI scanning. This study will further our understanding of neural activation patterns characteristic of the postpartum period and explore whether oxytocin buffers women against depression by inhibiting neural activation to negatively arousing stimuli in limbic brain regions to promote optimal maternal behavior. PUBLIC HEALTH RELEVANCE: The extreme psychosocial and physiological changes inherent to motherhood leave many women vulnerable to mood disorders during the year following the birth of an infant. Maternal mood disorders have negative consequences not only for the mother experiencing the depression, but also for her infant, partner, and family. An understanding of the functional neuroendocrinological changes that occur with motherhood, such as oxytocin-mediated inhibition of neural activity related to negative emotional arousal, is critical to promote optimal maternal care and protection from mood disorders during the postpartum period.